PROJECT SUMMARY In the United States alone, diabetes affects over 30 million people and costs a staggering $245 billion annually. A hallmark of diabetes is the loss of physical or functional ? cell mass. Recent data suggest that the intrinsic ? cell response to inflammatory and metabolic stress ultimately impacts ? cell function and survival. Aberrant microRNA (miRNA) expression has been demonstrated in the ? cell. MiRNAs have also been shown to serve as important regulators of ? cell development and function, implicating them in ? cell dysfunction during diabetes development. The long-term goal of this applicant is to establish an independent translational research career exploring diabetes pathophysiology as it relates to ? cells, and specifically focusing on the role of ? cell miRNAs in diabetes development. This application's central hypothesis is that ? cell microRNA-21 (miR-21) plays a critical role in inhibiting ? cell function and inducing loss of ? cell identity. Two specific aims are proposed to test this hypothesis. Experiments in Aim 1 will use an in vitro Tet-on INS1 lentiviral system of dose dependent miR-21 overexpression to carefully validate physiologic effects of increased ? cell miR-21 and delineate direct mRNA targets by which miR-21 exerts these effects. Effects on dedifferentiation/plasticity will be further evaluated using lineage tracing in a zebrafish model of miR-21 overexpression. Experiments in Aim 2 will test effects of miR-21 on ? cell function and identity in a mammalian system, using genetic mouse models of inducible miR-21 knockout and overexpression. Completion of these aims will, for the first time, define the role of pathologic cytokine- induced increases in ? cell miR-21 on ? cell function and identity. This F30 award entails a 4-year training plan designed to achieve 4 main objectives: 1) train in state-of-the-art techniques and concepts in diabetes research 2) train in the use of transgenic animal models for diabetes research 3) train in oral and written presentation of research findings, including grant preparation and 4) integrate clinical experiences with research training.The applicant will benefit from the outstanding and collaborative research environment provided by the Center for Diabetes and Metabolic Diseases at the Indiana University School of Medicine. Her training will also benefit from a mentoring and advisory committee consisting of a diverse team of carefully selected and established NIH funded investigators. The proposed training will provide the applicant with a fertile training environment in which she can develop an understanding of ? cell physiology and expand her molecular biology toolkit within an existing translational collaborative team.